1. Field of the Invention
This invention concerns the preparation of 1-hydroxycalciferol (that is 1-hydroxy Vitamin D) derivatives with special reference to the 1.alpha.-hydroxy derivatives. These compounds are well known to be highly active in combating many disorders of calcium metabolism.
2. Prior Art
Numerous preparation of 1.alpha.- and 1.beta.-hydroxy calciferol derivatives have been described. A brief list includes: 1.alpha.-hydroxycholecalciferol [DeLuca et al. U.S. Pat. No. 3,741,996; Barton et al. J.A.C.S. 95, 2748 (1973); Furst et al., Helvetica 56, 1708 (1973)]; 1.beta.-cholecalciferol [Mazur et al., J.O.C. 42, 3597 (1977); DeLuca et al., Chem. Comm., 890 (1977)]; 1.alpha.,25-dihydroxy cholecalciferol [DeLuca et al., Tetrahedron Letters, 4147 (1972); Barton et al., Chem. Comm. 203 (1974); Uskokovic et al., U.S. Pat. No. 3,993,675]; 1.beta.,25-dihydroxycholecalciferol [DeLuca et al., Chem. Comm., 890 (1977)]; 1.alpha.-hydroxyergocalciferol [DeLuca et al., Science 186, 1038 (1974)]; 1.alpha.,25-dihydroxyergocalciferol [DeLuca et al., Biochemistry 14, 1250 (1975)]; 1.alpha.,24 R and S-dihydroxycholecalciferols [lkekawa et al., J. C. S. Perkin l, 1421 (1975)]; 1.alpha. ,24 R and S, 25-trihydroxycholecalciferols [lkekawa et al., Chem. Pharm. Bull., 23, 695 (1975)].
This is by no means an exhaustive list but it is representative of the major approaches to the major 1-hydroxy derivatives of calciferol. A salient feature of almost all of these syntheses is that the 1.alpha.-hydroxy calciferol is derived from its 1.alpha.-hydroxy steroidal pro-vitamin isomer through the standard photochemical and thermal rearrangements of this system.
Two approaches avoid this undesirable photochemical transformation. One is that of Lythgoe et al. [J. C. S. Perkin 1, 2654 (1974)] which described a total synthesis of 1.alpha.-hydroxy-cholecalciferol. This is a lengthy synthesis and is of academic interest only not being at all suitable for large scale production, especially for the more highly substituted derivatives. The second is that of Pelc who describes the direct oxidation of cholecalciferol [Steroids 30, 193 (1977)], but the yield of the desired 1.alpha.-hydroxy-cholecalciferol is exceedingly low.